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To determine the effects of non-cholesterol based sterol enriched diets on liver gene expression

ABSTRACT: Xenosterol accumulation in mice deficient in sterolin function leads to significant toxicity, with infertility, decreased body fat accumulation, macrothrombocytopenia, cardiac fibrosis and premature death. The predominant xenosterols are phytosterols derived from the diet which includes a mixture of sitosterol (typically 70%), campesterol (~20%) and stigmasterol (~5-10%), and ergosterol found in fungi. To delineate whether ergosterol or stigmasterol could accumulate in Abcg8 knockout mice and demonstrate any signs of xenosterol toxicity, we designed two diets with one supplemented with ergosterol (>98% purity) and other with stigmasterol (>80% purity) and fed them to Abcg8 knockout mice. Over a 12-week period, both male and female Abcg8 knockout mice fed with either of the diets gained normal amounts of weight, body fat, showed no disturbances in tail-cuff measured blood pressure, and plasma analyses showed no abnormalities of platelet counts or volumes, blood glucose, or plasma cholesterol. Fertility testing showed no abnormalities. While stigmasterol accumulation was observed in the both plasma and tissues, elevated levels of ergosterol was not observed in plasma. However, there was a dramatic increase in plasma brassicasterol, with levels reaching 80 mg/dL in plasma. Our data concludes that either stigmasterol or ergosterol or brassicasterol accumulations in Abcg8 Knockout Mice does not account for xenosterol toxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE146522 | GEO | 2020/09/04

REPOSITORIES: GEO

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Project description:Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured biomarker inhibition and fetal-brain gene expression in wild-type (PON1+/+), PON1-knockout (PON1-/-), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75 or 0.85 mg/kg/d CPO from gestational days (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), RBC acylpeptide hydrolase (APH), plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1-/- and tgHuPON1Q192, but not PON1+/+ or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1-/- mice, but not in other genotypes. Pregnant mice (wild type (WT), PON1-knockout (KO), tgHuPON1R192 (R-tg) and tgHuPON1Q192 (Q-tg)) were exposed to various amounts of CPO (0, 0.5, 0.75 and 0.85 mg/kg/d) for 12 days (gestational days 6-17). On gestational day 18, dams were sacrificed and fetal brains were collected. A total of 264 fetal brains from 80 dams were processed to extract total RNA using TRIZOL and the QIAamp Tissue kit from QIAGEN. Microarray analysis was performed using the fetuses of 5 dams per experimental group (total RNA was pooled from individual fetal brains from each dam). The dams used for fetal-brain microarray analysis were selected using a random-number generator, after first eliminating dams with brain AChE activities > 1.5 SD compared to the mean for their treatment group. RNA samples isolated from individual fetal brains from each dam were combined, then labeled and hybridized to Affymetrix Mouse Gene 1.0 ST microarrays.

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To determine the effects of non-cholesterol based sterol enriched diets on liver gene expression

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